This invention relates to novel compositions for reduction of organic substrates, and processes for preparing and using the same.
There are a wide variety of reducing agents available for organic synthesis. For example, sodium borohydride, borane, lithium aluminum hydride and hydrogen are all employed to perform reductions industrially. Lithium aluminum hydride (LiAlH4) is a powerful reducing agent, soluble in organic solvents, and has found wide utility in organic synthesis. A wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitrites and imides. However, the expense of lithium aluminum hydride prevents its wider industrial employment.
A variety of synthetic methods exist for the commercial preparation of lithium aluminum hydride. One method involves the metathesis of sodium aluminum hydride (NaAlH4)with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1). Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3). There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.
LiCl+NaAlH4xe2x86x92LiAlH4+NaClxe2x80x83xe2x80x831.
Li+Al+2H2xe2x86x92LiAlH4xe2x80x83xe2x80x832.
LiH+Al+3/2H2xe2x86x92LiAlH4xe2x80x83xe2x80x833.
4 NaH+AlCl3+LiClxe2x86x92LiAlH4+NaClxe2x80x83xe2x80x834.
4 LiH+AlCl3xe2x86x92LiAlH4+3NaClxe2x80x83xe2x80x835.
All of these preparations are typically conducted in an organic solvent, such as toluene, diethyl ether, or tetrahydrofuran. Also, at the conclusion of the reaction, the reaction mixture is laboriously filtered to remove the unreacted starting materials and/or by-product inorganic salts. These filtrations are time consuming, the equipment is capital intensive, and some of the lithium aluminum hydride product adheres to the solids, which reduces the yield. The solid by-products and starting materials are very hazardous and must be handled, recycled, and quenched very carefully.
It has been discovered that a composition prepared from an active hydride, an additive, and a Lewis base, optionally in a hydrocarbon solvent, can provide a superior reducing system for organic substrates. For example, a composition prepared from 60 mole % tetrahydrofuran as the Lewis base, 10 mole % lithium chloride as the additive, 10 mole % sodium aluminum hydride as the active hydride, and 20 mole % toluene can afford excellent yields in standard organic reductions. In addition, the compositions of the invention are non-pyrophoric and are more thermally stable than pure THF solutions of sodium aluminum hydride (NaAlH4) or lithium aluminum hydride (LiAlH4).
The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less), typically from about thirty minutes to about four hours.
The present invention also provides processes for the reduction of organic substrates using the compositions of the invention.
Various active hydrides, including metal hydrides such as sodium aluminum hydride, trisodium aluminum hexahydride, and the like and mixtures thereof can be employed as the active hydride component. Examples of useful additives include, but are not limited to, lithium chloride, lithium bromide, aluminum trichloride, titanium tetrachloride, titanium tetrabromide, lithium alkoxides, lithium alkoxides of chiral alcohols (such as menthol), lithium dialkylamides, lithium dialkyl amides of chiral amines (such as (+) bis-[(R)-1-phenethyl]amine), and the like and mixtures thereof. Examples of useful hydrocarbon solvents include, but are not limited to, pentane, hexane, heptane, cyclohexane, decane, toluene, xylenes, ethylbenzene, cumene, cymene, and the like and mixtures thereof. Examples of useful Lewis bases include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl t-butyl ether (MTBE), 1,2-diethoxyethane, 1,2-dimethoxyethane, triethylamine, tributylamine, N, N, Nxe2x80x2, Nxe2x80x2-tetramethylethylenediamine (TMEDA), diisopropylethylamine, and the like and mixtures thereof.
Typical concentrations (mole %) of the components used to prepare the reducing composition of the invention are listed in the table below.
The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less) for a few hours, typically from about thirty minutes to about four hours.
In one advantageous embodiment of the invention, the novel composition is prepared by adding a slurry of sodium aluminum hydride/toluene to a slurry of lithium chloride/tetrahydrofuran. Because the addition is very exothermic, care should be taken. When using the specific reagents sodium aluminum hydride and lithium chloride, the reagents must be combined in a precise manner to result in reduction product yields comparable to that of lithium aluminum hydride. Otherwise, reduction product yields comparable to that of sodium aluminum hydride result.
When using sodium aluminum hydride as a starting material, the composition of the invention is also unique as it is prepared from a slurry of sodium aluminum hydride in hydrocarbon solvent (i.e., about 80 weight percent (wt %) or less sodium aluminum hydride) and a minimal amount of tetrahydrofuran, in contrast to solid or damp cake forms of sodium aluminum hydride. For example, the slurry can be a commercially available slurry of 40 wt % sodium aluminum hydride in toluene. The use of a hydrocarbon solvent alone, such as toluene, without a Lewis base, such as tetrahydrofuran, can hinder the preparation of this effective, novel composition.
Although not wishing to be bound by any explanation of the invention, it is believed that the composition of the invention can include starting materials, counterion exchange products, complexes of starting materials and/or counterion exchange products, and mixtures thereof.
The novel reduction composition of this invention can also be characterized by its particle size distribution. For example, typical particle size distribution of a novel reduction composition in accordance with the invention prepared from 56.9 mole % tetrahydrofuran as the Lewis base, 15.7 mole % lithium chloride as the additive, 12.6 mole % sodium aluminum hydride as the active hydride, and 14.8 mole % toluene was determined on a Malvern MasterSizer. The mean diameter for the reduction composition is around 350 xcexcm and the median is 400 xcexcm. By comparison, the particle size distribution of sodium aluminum hydride exhibits a mean diameter at 216 xcexcm and a median at 200 xcexcm. The particle size distribution of lithium chloride exhibits a mean diameter at 424 ,xcexcm and a median at 448 xcexcm.
It has also been found that this same representative reduction composition slurry sample can be analyzed for sodium, lithium and aluminum by ICP (Inductively Coupled Plasma) and for chloride by wet titration. This data confirms the appropriate proportions of NaAlH4 and LiCl combined during the preparation of this novel reduction composition. This is especially important when the sodium aluminum hydride charge cannot be accurately determined, for example, on large scale. Example ICP and chloride analyses are represented below. Chloride analysis is faster and combined with a hydride content analysis, should confirm the ratio of NaAIH4 and LiCl.
The thermal behavior of the novel reduction composition was studied in an RSST (Reactive System Screening Tool) and found to be more thermally stable than 10 wt % LiAlH4/THF or 40 wt % NaAlH4. The LiAlH4/THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 130xc2x0 C. Likewise, a NaAlH4/THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 220xc2x0 C. Whereas a similar experiment with a novel reduction composition mixture prepared from 9.7 mole % NaAIH4, 16 mole % LiCl, 10.4 mole % toluene and 63.9 mole % THF showed a rate acceleration/runaway behavior only when heated above 300xc2x0 C. These experiments demonstrate that the novel reduction composition formulation is safer and thus more stable than a 10 wt % LiAlH4/THF solution as well as a 40 wt % NaAIH4/THF solution.
In use, the organic compound to be reduced is added to the reduction composition of the invention under an inert atmosphere. Alternatively, the reduction composition can be added to the organic substrate, or the reduction composition and organic substrate added simultaneously. The reduction reaction proceeds under appropriate conditions at a temperature sufficient and for a time sufficient for the reduction reaction to proceed, generally at a temperature of about ambient to about the reflux temperature of the mixture for about one hour to about 24 hours. The reaction can be terminated by quenching the mixture, for example, by addition of water and aqueous NaOH and cooling. Work-up of the reduction reaction mixture and isolation of the reduced product can be accomplished using conventional procedures known in the art.
The compositions of the invention can be used for the reduction of a variety of organic compounds including without limitation aldehydes, ketones, esters, amides, epoxides, nitrites, and other imides. Exemplary compounds which can be reduced in accordance with the invention include (+/xe2x88x92) trans 3-ethoxycarbonyl-4-(4xe2x80x2-fluorophenyl)-N-methyl-piperidine-2,6-dione (to (+1-) trans 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine), N-methylsuccinimide, ethyl 1-methylnipecotate, and the like.
For example, typical reducing agents and yields are listed in the table below for the reduction of (+/xe2x88x92) trans 3-ethoxycarbonyl-4-(4xe2x80x2-fluorophenyl)-N-methyl-piperidine-2,6-dione to (+/xe2x88x92) trans 4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine.
It is reported in the literature that commercial sodium aluminum hydride (NaAlH4) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times, however, the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride, as demonstrated by the above table. See also Example 4 below, which demonstrates that use of sodium aluminum hydride alone as the reducing agent resulted in reduction product yields from 45 to 55%, using toluene/THF solvent mixtures and THF alone. Use of LiCl in limiting amounts (0.1 equivalent) also gave low yields (50%).
The inventors have found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives. Thus, in accordance with this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives as described above. For example, the additive lithium chloride could be mixed with sodium aluminum hydride in order to produce a resulting hydride composition that performs as well as lithium aluminum hydride alone.
It is also known that LiCl can be reacted with NaAlH4 in stoichiometric amounts to form lithium aluminum hydride, which is then separated from the by-product, NaCl, prior to use. This metathesis reaction, however, requires the addition of a catalyst, such as a small amount of LiAlH4, to initiate the reaction, or alternatively a NaAlH4 solution forming prestep. In this invention LiCl can be added in less than stoichiometric amounts, and without requiring LiAlH4 as a catalyst, or a NaAlH4 solution forming prestep. As discussed above, when the starting compounds include sodium aluminum hydride and lithium chloride, the order of addition of the additive is important. However, it is not currently believed that the order of addition of the additives is critical when using other starting materials, in which case it is currently believed that the additives can be added at various times during the entire reduction.
Although reductions performed with LiAlH4 provide better yields than when using NaAlH4 (i.e., NaAlH4 without additives may be less reactive in some cases), LiAlH4 is much more expensive than NaAlH4. Reductions of functional groups, especially imides, employing NaAIH4 in accordance with the invention, however, with the appropriate additives gave identical results as obtained when using the more costly commercial LiAlH4.
The present invention also describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents. This aspect of the present invention overcomes prior difficulties associated with the commercial preparation of lithium aluminum hydride. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction of functional groups, especially imides. Unfiltered lithium aluminum hydride prepared from sodium aluminum hydride and lithium chloride, or unfiltered lithium or sodium aluminum hydride prepared from the elements can be used directly in subsequent reduction of the substrate. If required for yield improvement, other additives can be added to the sodium aluminum hydride. The resulting unfiltered, in situ-prepared hydride reducing agents are used directly for reduction of a substrate in an organic solvent. Overall this process saves in number of filtration steps, causes filtrations to be safer, and reduces the handling large amounts of ethereal solvents required for the preparation of the reducing agent. The yields with the in situ reduction protocol are essentially identical to the yields obtained when the reduction is performed with filtered lithium aluminum hydride solution. Further, all functional groups that are typically reduced with filtered lithium aluminum hydride are reduced with the unfiltered lithium aluminum hydride solutions. Work-up of the reduction reaction and isolation of the reduced product involves employment of the standard procedure used for commercial lithium aluminum hydride. The inorganic by-products are most often removed by filtration or become part of any aqueous phase that may be present.
For example, reduction of (+/xe2x88x92) trans 3-ethoxycarbonyl-4-(4xe2x80x2-fluorophenyl)-N-methyl-piperidine-2,6-dione or (+/xe2x88x92) trans 3-methoxycarbonyl-4-(4xe2x80x2-fluorophenyl)-N-methyl-piperidine-2,6-dione with unfiltered lithium aluminum hydride afforded (+/xe2x88x92) trans-4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yields and with similar impurity profiles as with commercial LiAlH4. 
In another aspect of this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives. It is reported in the literature that commercial sodium aluminum hydride (NaAlH4) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride. It was found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives. For example the additive, lithium chloride, could be mixed with sodium aluminum hydride in order to produce a resulting hydride that performed as well as sodium aluminum hydride with the additive, lithium aluminum hydride, or lithium aluminum hydride alone. It is known that LiCl can be reacted with NaAlH4 in stoichiometric amounts to form lithium aluminum hydride (equation 1), which is then separated from the by-product, NaCl, prior to use. In this invention it was found that it is unnecessary to filter the NaCl prior to use of the in situ formed lithium aluminum hydride. Also, in this invention LiCl can be added in less than stoichiometric amounts and the NaCl is not separated from the resulting hydride. This invention shows that this filtration is unnecessary. The additives can be added at various times during the entire reduction. Although NaAlH4 without additives may be less reactive in some cases, it is superior due to the high cost of LiAlH4. Reductions of functional groups, especially imides, employing NaAlH4 with the appropriate additives gave identical results as obtained when using the more costly, commercial LiAlH4. 
For example, reduction of (+/xe2x88x92) trans 3-ethoxycarbonyl-4-(4xe2x80x2-fluorophenyl)-N-methyl-piperidine-2,6-dione with in situ modified NaAIH4 afforded (+/xe2x88x92) trans-4-(4xe2x80x2-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and with similar impurity profile as with commercial LiAlH4.
Optionally, inorganic or organic additives can be added to either reduction protocol to aid the reduction. These additives can be employed in 0.01 equivalents up to and including 5 equivalents. Examples of useful additives, which can be used in combination as well, include, but are not limited to LiCl, HCl, LiBr, AlCl3, TiCl4, AlBr3, TiBr4, LiAlH4, NaBH4, LiBH4, LiBH(R)3, NaBH3 (anilide), THF-BH3, LiAlH(OMe)3, LiAlH(O-t-Bu)3, NaAlH2 (OC2H4OCH3), AlH3; ethers such as methyl t-butyl ether, dimethoxyethane, glymes; alcohols such as methanol, ethanol, isopropanol, t-butanol, ethereal alcohols and/or their corresponding metal alkoxides; primary and/or secondary amines both aromatic and/or aliphatic and their corresponding metal amides; and tertiary amines such as tetramethylethylene diamine, triethylamine.